Emerging Pharmacotherapy of Tinnitus

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Expert Opin Emerg Drugs. Author manuscript; available in PMC 2010 December 1.
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Expert Opin Emerg Drugs. 2009 December ; 14(4): 687702. doi:10.1517/14728210903206975.
Emerging pharmacotherapy of tinnitus

Berthold Langguth,
Department of Psychiatry and Psychotherapy, University of Regensburg, Germany; Interdisciplinary
Tinnitus Clinic, University of Regensburg, Germany. University of Regensburg,
Universitaetsstrae 84, 93053 Regensburg, Germany, Phone: +49-941-941 2099, Fax:
+49-941-941 2025
Richard Salvi, and
Center for Hearing and Deafness, Department of Communicative Disorders and Sciences,
University at Buffalo, Center for Hearing and Deafness, 137 Cary Hall, Buffalo, NY 14214, Phone:
716 829 5310, Fax: 716 829 2980
Ana Beln Elgoyhen

Instituto de Investigaciones en Ingeniera Gentica y Biologa Molecular, Consejo Nacional de
Investigaciones Cientficas y Tcnicas, Buenos Aires 1428, Argentina. Departamento de
Farmacologa, Facultad de Medicina, Universidad de Buenos Aires, Buenos, Aires 1121, Argentina,
Instituto de Investigaciones en Ingeniera Gentica y Biologia Molecular, (INGEBI-CONICET),
Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina; phone: +5411 4 7832871; fax: +5411 4
7868578
Berthold Langguth: Berthold.Langguth@medbo.de; Richard Salvi: salvi@buffalo.edu; Ana Beln Elgoyhen:
elgoyhen@dna.uba.ar
Abstract
Tinnitus, the perception of sound in the absence of an auditory stimulus, is perceived by about one
in 10 adults, and for at least 1 in 100, tinnitus severely affects their quality of life. Since tinnitus is
frequently associated with irritability, agitation, stress, insomnia, anxiety and depression, the social
and economic burdens of tinnitus can be enormous. No curative treatments are available. However,
tinnitus symptoms can be alleviated to some extent. The most widespread management therapies
consist of auditory stimulation and cognitive behavioural treatment, aiming at improving habituation
and coping strategies. Available clinical trials vary in methodological rigor and have been performed
for a considerable number of different drugs. None of the investigated drugs have demonstrated to
provide replicable long-term reduction of tinnitus impact in the majority of patients, in excess of
placebo effects. Accordingly, there are no FDA- or EMEA-approved drugs for the treatment of
tinnitus. However, in spite of the lack of evidence, a large variety of different compounds are
prescribed off-label. Therefore, more effective pharmacotherapies for this huge and still growing
market are desperately needed and even a drug that produces only a small but significant effect would
have an enormous therapeutic impact. This review describes current and emerging
pharmacotherapies with its current difficulties and limitations. In addition, it provides an estimate of
the tinnitus market. Finally, it describes recent advances in the tinnitus field which may help
overcome obstacles faced in the pharmacological treatment of tinnitus. These include incomplete
knowledge of tinnitus pathophysiology, lack of well established animal models, heterogeneity of
Correspondence to: Berthold Langguth, Berthold.Langguth@medbo.de.

Declaration of interest: B Langguth is supported by the Deutsche Forschungsgesellschaft and the Tinnitus Research Initaitive; R Salvi
is supported by grants from NIH (R01DC009091 and R01DC009219, RS) and Tinnitus Research Initiative; AB Elgoyhen is supported
by the Tinnitus Research Initiative and a Howard Hughes International Scholar Grant.
Langguth et al.
Page 2
different forms of tinnitus, difficulties in tinnitus assessment and outcome measurement and
variablility in clinical trial methodology.
Keywords
Auditory system; hearing; phantom perception; pain; inner ear; antidepressants; anticonvulsants;
anxiolytics; GABA; NMDA; glutamate
1. Background

Tinnitus can be differentiated in two broad categories. Objective tinnitusor somatosound

refers to the rare number of cases in which a sound source can be identified. Examples include
abnormal blood flow pulsations in vessels adjacent to the middle ear or abnormal rhythmic
muscle contractions as in palatal myoclonus (1). In contrast, subjective tinnitus, sometimes
referred to as a phantom auditory perception, refers to the much more common form in which
the source of the auditory sensation cannot be identified. Henceforth, this condition will be
referred to simply as tinnitus. Tinnitus can take a variety of forms including tonal, hissing,
ringing, whistling or cricket-like sound. Tinnitus is prevalent in the general population, with
approximately 1015% experiencing it in some form. Even if most people can learn to ignore
the phantom sound, in about 13%, tinnitus severely affects their quality of life (2;3). Thus,
for approximately 13 million people in western Europe and the USA, tinnitus negatively affects
their life to the extent that they seek medical advice and treatment (4). Although certain
common trends are found across the patient population, tinnitus can have many different
underlying causes. In particular, it often co-occurs with sensorineural hearing loss which might
explain its increasing prevalence with age (3). However, tinnitus can be associated with
virtually all disorders affecting the auditory system. Numerous studies report that the pitch of
the tinnitus sensation matches the region of the hearing loss (57). These findings suggest that
tinnitus arises in the central nervous system as a consequence of reduced auditory input from
a partly deafferented cochlea. This resembles to some extent the pathophysiologic mechanisms
involved in the generation of phantom pain after limb amputation. This notion is further
supported by the observation that tinnitus persists even after transection of the auditory nerve
(8). In addition, acute reduction of auditory input to very low levels leads to tinnitus-like
phantom sounds (9;10). However, all those with hearing disorders perceive tinnitus. It has been
recently shown that the risk of developing tinnitus depends on the exact slope of the audiogram.
A steep slope of the audiogram might lead to abrupt discontinuities in the activity along the
tonotopic axis with increased risk for the occurrence of tinnitus (7). Conversely, tinnitus can
also occur in people with clinically normal hearing in the 2508000 Hz range, although hearing
loss cannot be ruled out by a normal audiogram, especially if it occurs between 800020,000
Hz. In a survey of over 2000 tinnitus patients, Henry et al (1) reported that prolonged noise
exposure and noise trauma were an associating factor for the majority of cases (22%), followed
by head and neck injury (17%), infections and neck illness (10%) and drugs and other medical
conditions (13%). The remaining could not identify any specific known event associated with
their tinnitus onset.
Tinnitus can be either a transient experience or a persistent chronic disorder. Similar to chronic
pain, tinnitus is a purely subjective phenomenon and therefore extremely difficult to evaluate
(11). Tinnitus assessment procedures often involve a description of its perceptual
characteristics such as temporal duration, spatial lateralisation, loudness, pitch, masking
characteristics and sensitivity to residual inhibition (12). In addition, the amount of distress,
annoyance, and impact on daily living is important. Usually, the subjective tinnitus intensity
is estimated by application of a visual analogue scale (VAS) or a numeric rating scale (NRS)
for intensity. Objectively quantifying tinnitus is attempted by matching or masking methods.
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Matching is achieved by offering different tones to the patient and asking what frequency and
intensity best fit their tinnitus. When matching the tinnitus to an external sound presented to
the ear without tinnitus, the vast majority of the patients rate their tinnitus as less than 510
dB above hearing threshold expressed as dB sensation level (dB SL) (13). Masking, the
estimation of the minimum noise level required to mask the tinnitus, has been shown to be
more reliable for assessment of tinnitus loudness (14). However, it has to be taken into
consideration that the tinnitus of some patients cannot be masked at all.
The handicap and the amount of distress that tinnitus evokes is assessed by validated self-report
tinnitus questionnaires in the majority of studies (11). However, there is only a poor correlation
between the intensity of the tinnitus as qualified by matching or masking techniques and the
degree of annoyance the tinnitus creates (15). The poor correlation between tinnitus loudness
and the perceived annoyance points to an important role of non-auditory factors such as emotion
or attention (16;17).
Although the exact pathophysiological mechanisms underlying different forms of tinnitus are
still not completely understood, there is growing evidence that changes in neuronal activity in
different parts of the auditory pathway, including the dorsal cochlear nucleus, inferior
colliculus, thalamus and/or auditory cortex underlie tinnitus pathology (1825). A decrease in
inhibition and/or increase in excitation may lead to an excitatory-inhibitory imbalance that can
cause neural hyperexcitability in these regions leading to the perception of phantom sounds.
Neuronal excitability can be modulated by different neurotransmitters and neuromodulators
that act on voltage- or ligand-gated channels. So there is no reason to believe that the neural
activity underlying tinnitus cannot be pharmacologically targeted. The fact that intravenous
lidocaine, a local anesthetic that blocks voltage-gated sodium channels (26), can lead to the
temporary reduction or total disappearance of tinnitus in 70% of patients (27) is a proof of
principle.
2. Medical need
The greatest medical need arises from the 1 to 3% of the population that is severely affected
by tinnitus, with major negative impact on quality of life (2). Severe tinnitus is frequently
associated with depression, anxiety and insomnia (28;29). Moreover, tinnitus incidence is
increasing dramatically with industrialization and longer lifespan. In developed countries the
increase of leisure noise is expected to increase the incidence of hearing loss and tinnitus (4;
30;31). Tinnitus is a frequent work-related disability and the financial burdens it imposes on
governments and industries are significant. The US Veterans Administration Benefits Report
ranked tinnitus as the second most prevalent service related disability. Among those who began
receiving benefits in 2006, tinnitus was ranked first among service related disability,
accounting for 9.7% of the total (http://www.vba.va.gov/bln/21/). In 2006, the annual
compensation for tinnitus related disability was $536 million.
Despite the significant clinical need for effective treatment of tinnitus, there is currently no
single FDA- or EMEA-approved drug on the market. A review of controlled clinical trials of
tinnitus published in 1999 (32) concluded that no studied drug provides replicable, long-term
reduction of tinnitus impact, in excess of placebo effects. Unfortunately, this has not changed
during the last ten years (33).
For the majority of tinnitus sufferers that seek medical advice, the treatment goals are aimed
at symptomatic relief, since causally oriented therapeutic strategies are lacking. The most
frequently used therapies consist of auditory stimulation and cognitive behavioral treatment
aimed at improving habituation and coping strategies. Importantly, over 4 million prescriptions
are written each year in Europe and the US for tinnitus relief (34), but these are all off-label
prescriptions from a wide variety of therapeutic drugs with uncertain efficacy. In addition, a
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large, undocumented group of tinnitus patient self-medicate with a plethora of nutriceutical

compounds that do not require a prescription. Most clinicians who treat tinnitus patients would
welcome an evidence-based effective drug therapy targeted at tinnitus. Thus, there is a pressing
need to identify drugs that can provide significant tinnitus relief. Since in some individuals,
tinnitus causes irritability, agitation, stress, depression, insomnia and interferes with normal
life, even a drug that produces a small but significant effect would have a huge therapeutic
impact. However, a drug that leads to the disappearance of tinnitus should be the ultimate goal.
3. Existing treatments
A large variety of pharmacological agents are used for the treatment of tinnitus (Table 1). Some,
but not all of the drugs in Table 1 have been examined in clinical trials. However, there is
considerable variability in the methodologic rigor of the different trials. Shortcomings in trial
methodology include lack of placebo-controlled double-blind design, use of inadequate
outcome measures, short duration of clinical trials, and lack of follow-up periods or large
dropout rates. There is no drug which has been specifically developed to treat tinnitus. Some
agents have been used to target symptoms frequently associated with tinnitus such as
depression, anxiety or insomnia. Other substances have been investigated either based on
pathophysiological hypotheses, on serendipitous clinical observations or due to their efficacy
in clinical conditions that are thought to share pathophysiologic similarities with tinnitus, such
as epilepsy (35) or central pain (36). It is worth mentioning that some of the pathophysiologic
hypotheses, such as the putative involvement of cochlear vascularisation, are highly
speculative. Thus, results from pharmacologic interventions may also be useful for either
confirming or rejecting the hypotheses underlying their use.
It seems unlikely that there will be one single drug which will cure all forms of tinnitus. It is
likely that many subtypes of tinnitus exist and that each will require a different form of
treatment. Thus, one of the pressing needs in tinnitus research is a scheme to classify patients
into subtypes that might respond positively to a specific drug treatment. Indeed, some drugs
have been reported to provide moderate relief of symptoms in a subset of patients. Careful
clinical observations along with data from clinical trials have provided useful clues for deciding
on a rational course of drug therapy for selected patients. However, apart from intravenous
lidocaine, which transiently suppresses tinnitus in a significant subgroup of patients (27), but
which cannot be used for long-term treatment, no drug has been proven sufficient effectiveness
in at least two randomized controlled clinical trials. The fact that positive results in some trials
could not be replicated by following trials may be due to methodological shortcomings in many
studies, such as the lack of proper control groups or small sample sizes. A further explanation
for negative or dissimilar results across studies may be the pathophysiologic heterogeneity of
tinnitus (37), highlighting the importance of subgrouping tinnitus according to the underlying
pathophysiology. Drugs investigated to suppress tinnitus will be reviewed in the following
sections in detail.
3.1. Lidocaine
Already in 1935, lidocaine was found to suppress tinnitus following nasal administration
(38). Since then, many clinical studies have confirmed transient tinnitus suppression by
intravenous administration in 4070% of tinnitus subjects (3941). The effect seems to be dose
dependent with suppression of tinnitus occurring at free arterial plasma concentrations from
1.75 to 3.5 mol/L, whereas concentrations above 3.5 mol/L may induce tinnitus (42). The
mechanisms of action by which intravenous lidocaine suppresses tinnitus are only incompletely
understood, but there is evidence that it affects both the cochlea and the central nervous system
(22;43;44). A recent study has demonstrated, that lidocaine can suppress tinnitus even after
transection of the auditory nerve (44). Lidocaine is generally used as a local anesthetic or to
treat cardiac arrhythmias (45). The mode of action of lidocaine is complex. It binds to fast
Langguth et al.
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voltage-gated sodium channels, reducing the magnitude of the sodium current during
depolarization (4648). It also affects calcium, potassium, and glycine-evoked chloride
currents (49). In human brain imaging studies in which lidocaine decreased the loudness of
tinnitus, the changes in loudness were associated with altered neural activity in the right
auditory association cortex (22;50). Since the effects of lidocaine are short lived and due to its
potentially life threatening arrythmogenic side effects, lidocaine is not an option for long-term
treatment. Oral analogues of lidocaine such as tocainide have been evaluated as a potential
long-term therapy for tinnitus. However, several randomized, controlled studies found that
tocainide had little benefit for tinnitus (5153), so it has been assumed that the tinnitus
suppressing action of lidocaine is not due to the sodium channel blocking activity common to
these two drugs.
3.2. Benzodiazepines
Several benzodiazepines have been tested for the treatment of tinnitus. Benzodiazepines bind
to the benzodiazepine site of the GABAA receptor where they act as allosteric modulators,
potentiating the action of GABA and thus increasing the permeability of chloride ions leading
to hyperpolarization and decreased excitability (54). The different benzodiazepines differ in
their half-life and are used as sedatives, anxiolytics, anticonvulsants and muscle relaxants.
Alprazolam, a short-acting triazolobenzodiazepine has been investigated for tinnitus treatment
in a prospective, double blind placebo controlled study (57). Alprazolam reduced tinnitus
loudness in 65% of subjects compared to 5% in the control group. Even if these results seem
encouraging, caution in the interpretation of these data is warranted because of the lack of
assessment of emotional aspects, the small sample size of 40 patients and the lack of replication
(32). Diazepam, a longer acting benzodiazepine was evaluated in a pilot trial involving 21
tinnitus patients (58). In contrast to alprazolam, which has a very similar mechanism of action,
diazepam had no effect on tinnitus loudness. One possible explanation for the discrepancy was
that the dose of alprazolam, but not diazepam, was adjusted for each patient to maximize its
effects on tinnitus (57).
Further data is available from a large retrospective study of clonazepam, a long acting
benzodiazepine. Medical records from over 3000 patients taking clonazepam (0.51 mg/day,
60180 days) for vestibular or cochleovestibular disorders revealed improvement of tinnitus
in 32% (59). In a prospective, randomized, single-blind clinical trial involving 10 patients per
group, clonazepam significantly reduced tinnitus loudness and annoyance relative to the
control group (60), however replication is needed because of the small sample size and the lack
of double blinding. Clinical use of benzodiazepine is limited by their side effects such as high
risk of drug dependency and personality changes. Moreover, caution is warranted since
protracted tinnitus has been reported after discontinuation of benzodiazepines (55;56).
3.3. Antidepressants
The tricyclic antidepressants nortriptyline, amitriptyline and trimipramine have been
investigated for the treatment of tinnitus. Beside their antidepressant properties, tricyclics have
been shown to be highly efficient for the treatment of chronic pain, which is of interest in view
of the proposed etiological similarities between tinnitus and neuropathic pain (36;61).
Amitriptyline inhibits the reuptake of serotonin and noradrenaline almost equally, whereas
nortriptyline inhibits mainly the reuptake of norepinephrine and to a lesser extent serotonin.
Trimipramine differs in its mode of action from other tricyclic antidepressants in that it blocks
postsynaptic dopamine and serotonin receptors (62).
One study compared amitriptyline with placebo and found that 6 weeks with amitriptyline at
100 mg per day significantly reduced tinnitus complaints and tinnitus loudness compared to
the placebo group (63). In another study, where amitriptyline was compared with biofeedback,
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27.5% of patients reported improvement with amitriptyline while 43.5% reported improvement
with biofeedback revealing the superiority of biofeedback (64). In a small scale, single-blind,
placebo-washout study involving patients with severe tinnitus and major depression,
nortriptyline significantly reduced depression, and tinnitus loudness (10 dB reduction) (65).
These positive results in tinnitus patients with depression were confirmed in a double-blind
placebo-controlled follow up study (66). There was a significant correlation between the
reduction in tinnitus disability scores and depression scores (67) suggesting that positive effects
on tinnitus may mainly be a consequence of nortriptylines antidepressant effect. Trimipramine
was evaluated in a small double blind, placebo crossover study (68), which did not demonstrate
a difference between trimipramine and placebo treatment. Interestingly, tricyclic
antidepressants have also been repeatedly found to induce tinnitus (6971). Serotonin reuptake
inhibitors have also been investigated for the treatment of tinnitus. Paroxetine was investigated
in a double-blind, placebo-controlled study involving chronic tinnitus patients without
comorbid depression. In this study paroxetine was not superior to placebo in its effect on
tinnitus loudness and Tinnitus Handicap Questionnaire scores (72). Sertraline, a serotonin
reuptake inhibitor, which also inhibits the dopamine transporter, has been studied in a
randomized, double-blind placebo-controlled trial of patients with comorbid depression and
anxiety. Sertraline was found to be more effective than placebo in reducing tinnitus loudness
and Tinnitus Severity, but not tinnitus annoyance (73). Collectively, the results suggest that
tinnitus patients with depression and anxiety may benefit from antidepressants (74). However,
this effect may not to be a direct effect of antidepressants on tinnitus severity, but rather due
to the beneficial effect of antidepressants on comorbid depression and anxiety.
3.4. Anticonvulsants
The anticonvulsant carbamazepine which binds to voltage-gated sodium channels and
stabilizes the sodium inactivation state, thereby reducing neural firing (75;76), has been
investigated for tinnitus with mixed results. Based on the assumption that carbamazepine
resembles lidocaine in its mechanisms of action, three studies investigated the effect of
carbamazepine in tinnitus patients who previously had responded to intravenous lidocaine
(41;77;78). About half of these patients had a positive response to carbamazepine (6001000
mg daily). On the other hand, several randomized clinical trials reported no beneficial effect
of carbamazepine on tinnitus, which may be due to the low dosages (200 mg/day) used in these
studies (7981). A rare group of patients that receives significant benefit from carbamazepine
are those who have intermittent tinnitus that is caused by vascular compression of the auditory
nerve and which is characterized by sounds like a typewriter, pop corn or ear clicking (82;
83). In rats, carbamazepine was found to suppress salicylate induced tinnitus at a dosage of 15
mg/kg, but not by lower or higher doses (84).
The anticonvulsant gabapentin, which acts on voltage-gated calcium channels, is used for the
treatment of neuropathic pain and migraine. Pilot studies (85;86) and an animal study (87) have
suggested positive effects. However, several large, randomized clinical trails failed to
demonstrate benefit of gabapentin over placebo in treating tinnitus (8891). Vigabatrin and
tiagabine, two anticonvulsants that act on different aspects of GABAergic neurotransmission
have been studied in noise-exposed rats with behavioral evidence of tinnitus. Whereas
tiagabine had no effect, vigabatrin suppressed noise-induced tinnitus and tinnitus reappeared
when vigabatrin treatment was stopped (92). Unfortunately, vigabatrin can cause irreversible
visual field deficits in some patients, therefore the practical use of vigabatrin in humans is very
restricted (93).
3.5. Antiglutamatergic agents
Excitotoxicity mediated by NMDA receptors has been proposed as a mechanism for cochlear
tinnitus (9496). Moreover, an imbalance between inhibitory versus excitatory
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neurotransmission has been observed in several regions of the auditory pathway in tinnitus
(19). High doses of salicylate reliably induce tinnitus and augment currents through NMDA
receptors on cochlear spiral ganglion neurons (97;98). NMDA antagonists applied locally to
the inner ear blocked behavioral evidence of salicylate-induced tinnitus (95). Cochlear
application of a selective NMDA antagonist in the first four days following noise exposure
also reduced the probability of developing noise-induced tinnitus (96).
Caroverine, a spasmolytic drug, which is an antagonist of non-NMDA and NMDA glutamate
receptors (99), has been investigated in patients with putative cochlear tinnitus. Patients were
randomized to receive either caroverine (i.v., maximum dose 160 mg) or placebo. Within the
caroverine group, 63% showed a reduction in loudness immediately after treatment and 43 %
still showed improvement one week later, whereas there was no improvement in the placebo
group (100). However these encouraging results could not be replicated by a subsequent study
that followed the same protocol (101).
Memantine, which is approved for the treatment of Alzheimers disease, is a voltage-dependent

antagonist of NMDA receptors and reduces excitotoxicity by reducing calcium influx (102).
In addition, it blocks serotonin and nicotinic acetylcholine receptors (103;104). In contrast to
the positive results seen with cochlear application of NMDA antagonists, systemic memantine
failed to reduce tinnitus both in an animal study (105) and in a relatively large human
prospective, randomized, double-blind crossover study (106). Flupirtine, an NMDA antagonist
with analgesic properties has been investigated in a small open trial where it did not show any
beneficial effect (107).
Acamprosate influences the balance between GABAergic and glutamatergic transmission by
blocking NMDA receptors and enhancing GABAergic transmission (108). It is approved for
the treatment of alcoholism. With the rationale that reduced GABAergic inhibition and
increased glutamatergic excitation in the auditory pathways are involved in tinnitus generation,
the efficacy of acamprosate has been investigated. In a double-blind placebo-controlled study,
in which most patients suffered from noise-induced hearing loss, acamprosate (333 mg, 3 times
per day) resulted in a significant reduction of tinnitus loudness after 90 days of treatment
(109). A larger clinical trial has been initiated to assess the encouraging results from this
preliminary study (http://clinicaltrials.gov/ct2/show/NCT00596531).
3.6. Dopaminergic/antidopaminergic agents
Both dopaminergic and antidopaminergic drugs have been proposed for treating tinnitus. On
the one hand dopamine is an inhibitory transmitter in the cochlea; on the other hand
antidopaminergic drugs improve thalamic filtering of sensory signals. Furthermore,
dopaminergic pathways in limbic and prefrontal areas may be involved in mediating emotional
aspects of tinnitus (110112). Sulpiride, an antipsychotic drug that selectively blocks dopamine
D2 receptors (113) significantly reduced subjective ratings of tinnitus and tinnitus visual
analogue scores in one double-blind, placebo-controlled study. However, the reductions with
sulpiride were not significantly lower than those in the placebo group. Two further studies
investigated combinations of sulpiride with melatonin or with hydroxyzine. Both combinations
were significantly more effective in reducing tinnitus visual analogue scale and tinnitus
perception scores than placebo (114;115). The dopamine agonist piribedil was evaluated in a
515 elderly patients; 20% were reported to show complete resolution of memory impairment,
vertigo and tinnitus while 73% showed improvement. (116). While these results are
encouraging the lack of controls leave many questions unanswered. Piribedil was investigated
recently in a double-blind placebo-controlled cross-over study. Results showed that piribedil
was not superior to placebo, however a post-hoc analysis suggested that a subgroup of patients
with specific findings in electrocochleography may benefit from piribedil (117).
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3.7. Other Compounds
A large variety of drugs from different pharmacological classes is currently prescribed for
tinnitus (see Table 1), in spite of the fact that for a large number of them no data from clinical
trials is available. Here we will review only those compounds, for which clinical studies have
been performed.
Systemic and intratympanic steroids have been proposed for the treatment of acute tinnitus,
especially if it is related to sudden onset of hearing loss (118120). Although some studies
report positive results in subset of patients, the value of steroids in the treatment of idiopathic
sudden sensorineural hearing loss remains unclear since the evidence from randomized
controlled trials are contradictory in outcome (121).
Ginkgo biloba contains bioactive flavonoids and terpenes with vasoactive and antioxidant
properties and has been proposed for the treatment of a wide range of disorders including
tinnitus (122). Even though some studies have suggested beneficial effects of gingko on
tinnitus, particularly in patients with short duration symptoms (123;124), there is a growing
body of evidence from large, well controlled, double-blind, placebo-controlled clinical studies
clearly indicating that gingko is no more effective in alleviating tinnitus symptoms than placebo
(125127).
Melatonin, a naturally occurring circulating hormone, binds to melatonin receptors and plays
an important role in regulating circadian rhythms (128;129). Melatonin is also a potent
antioxidant that protects mitochondrial and nuclear DNA (130) and has been suggested to
protect against noise- and drug-induced hearing loss (131;132). Since sleep disturbances
represent a major complaint and complicating factor in tinnitus, melatonin was evaluated as a
treatment for tinnitus in three studies. An open label study found statistically significant
improvements on ratings of tinnitus severity and sleep quality (133), whereas a double-blind,
placebo-controlled cross over study did not demonstrate superiority of melatonin over placebo
(134). A more recent, randomized, placebo-controlled double-blind study found that melatonin
in combination with sulpiride reduced subjective ratings of tinnitus and tinnitus loudness more
than placebo (114).
Zinc, an essential trace metal plays an important role in numerous biological signaling functions
and is widely distributed in the auditory pathway (135;136). While positive results have been
reported in some patients with hypozincemia, zinc therapy did not result in tinnitus
improvement in patients with normal zinc levels in several double-blind, placebo-controlled
studies (137140).
Misoprostol is a synthetic prostaglandin E1 analogue which is primarily used to prevent gastric

ulcers induced by non-steroidal anti-inflammatory drugs (141). In a small, placebo-controlled
cross-over study, tinnitus severity improved in 33% of subjects during misoprostol treatment
(dose escalating to 800 g/day), while none improved with placebo (142). Two subsequent
double-blind placebo-controlled studies have shown a significant reduction of tinnitus loudness
with misoprostol treatment, but no differences in subjective measures of tinnitus severity
(143).
Atorvastatin reduces the synthesis of cholesterol by inhibiting HMG-CoA reductase and is
used to lower blood cholesterol and prevent vascular events (144). In a randomized, doubleblind placebo-controlled study over 13 months involving elderly patients with elevated
cholesterol, atorvastatin failed to slow the progression of age-related hearing loss or to
significantly reduce tinnitus (145).
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Nimodipine, a calcium antagonist, which crosses the blood-brain barrier and blocks L-type
calcium channels (146) is primarily used in the treatment of subarachnoid hemorrhage (147).
Pilot studies also suggest beneficial effects in mood disorders (148). In animal studies
nimodipine significantly reduced tinnitus related behavior caused by high doses of quinine or
sodium salicylate (149). The first open clinical trial suggested positive effects of nimodipine
on tinnitus in some patients (150). However, these results could not be confirmed in a second
open clinical trial (151).
Furosemide is a loop inhibiting diuretic used to treat congestive heart failure and edema
(152). Furosemide inhibits the Na-K-2Cl cotransporter (153), which is expressed in the inner
ear as well as in the brain (154;155). Furosemide has been proposed as a treatment for tinnitus
of cochlear origin because it strongly suppresses the endolymphatic potential and other
cochlear responses (156). In one study, approximately 50% of patients reported a reduction of
tinnitus symptoms following intravenous furosemide treatment. Furosemide has also been
found to suppress tinnitus in approximately 40% of patients with Menieres disease (157). In
contrast to these positive findings, high doses of furosemide have also been found to induce
temporary hearing loss and tinnitus (158;159).
Osmotic drugs such as mannitol or glycerol have been investigated in tinnitus. However, in an
open trial tinnitus was only relieved in 13.1% of patients treated with glycerol and 5.8% of
those treated with mannitol (160).
Scopolamine, which acts as a competitive antagonist of M1 muscarinic acetylcholine receptors,
is used to treat motion sickness, nausea and intestinal cramps (161;162). In an animal study,
high doses of salicylate, which induces tinnitus, increased the expression of c-fos and arg3.1
in the auditory cortex suggesting that they were biomarkers of tinnitus. Administration of
scopolamine suppressed the expression of c-fos and arg3.1 in the auditory cortex suggesting
that scopolamine might be a treatment for tinnitus (163). However, when behavioral measures
of tinnitus were obtained from rats, scopolamine failed to suppress behavioral evidence of
salicylate-induced tinnitus (164).
Cyclandelate, a vasodilator that is believed to act by blocking calcium influx (165), has been
investigated for the treatment of tinnitus based on the assumption, that some forms of tinnitus
may arise from cerebrovascular insufficiency. In an open, multi-centric clinical trial of patients
with tinnitus, vertigo and visual disturbances, 90-day treatment with cyclandelate reduced the
severity and frequency of these symptoms with minimal side effects (166). However, in a
subsequent placebo-controlled, double-blind study cyclandelate did not significantly change
audiometric measures of tinnitus loudness and pitch and caused side effects in many patients
(167).
Botulinum toxin has been investigated in a small pilot study, where it has demonstrated
superiority over placebo (168). Botulinum toxin has also been shown to be highly effective in
the rare cases where tinnitus is caused by palatal tremor (169).
4. Market review
Although there are no FDA or EMEA approved drugs to treat tinnitus, a potential market for
such drugs is just beginning to emerge. No published market research data on the use of drugs
to treat tinnitus could be located. Some relevant market data are available from a Tinnitus
Market Situation Analysis, which was prepared by the Royal National Institute of Deafness
in 2003 (34). Data about drug prescriptions related to tinnitus (as provided by IMS Health and
only reflecting drugs prescribed in primary care) illustrate the variation in prescribing habits
between different countries, which reflects the lack of availability of an effective treatment.
Based on epidemiologic data, customer research and market data of some products used for
Langguth et al.
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tinnitus management, the Royal National Institute of Deafness estimated the patient
opportunity for a tinnitus drug would be 8.2 million in 2003 and increasing to 15 million by
2012. The market value of Tinnitus Retraining Therapy and off-label pharmaceuticals was
estimated in 2003 to be 127 million US $. The market value of the whole segment symptomatic
relief from tinnitus was estimated to be 1.1 billion US $, with a huge potential to increase if
an effective drug for the relief of tinnitus was to become available. This can be explained by
the large number of people with tinnitus who have stopped seeking medical treatment because
of the lack of effect treatment option, but who would likely be interested in treatment as soon
as an effective compound is be available (34).
5. Current research goals

There is widespread recognition that consistency between research centers in the ways that
patients with tinnitus are assessed and how interventions outcomes are measured would
facilitate more effective cooperation and more meaningful evaluations of tinnitus treatments
(11).
Advances in neuroimaging are expected to contribute to better characterization of the neuronal

correlate of tinnitus and to the identification of new targets for treatment (170). A further
potential application is the differentiation between different forms of tinnitus. It is assumed,
that differences in the perceptual characteristics of tinnitus, in the emotions surrounding
tinnitus, and in the response to specific treatments are reflected by specific patterns of neural
activity, which could be detected by the use of imaging techniques. By contributing to
differential diagnosis, imaging may also serve as a predictor for specific treatments.
Furthermore, neuroimaging can be used for the assessment of the neuronal mechanisms by
which specific treatments exert their effects. This knowledge, in turn, can be useful for
improving efficacy of those treatment interventions.
One major limitation to the development of drugs to treat tinnitus and its associated emotional
symptoms has been the lack of in vitro bioassays or validated animal models in which to test
or screen for compounds. Several animal models have been developed which are based on
induction of tinnitus-like behaviors with noise exposure or on the administration of salicylate
(87;97;164;171). However, it remains to be determined to what extent data from drug trials in
the available animal models can be extrapolated to efficacy in humans.
6. Scientific rationale
There is compelling evidence, that tinnitus is related to alterations of neural activity in the
central nervous system. These alterations are most probably due to altered sensory input, e.g.
by cochlear pathologies. However, most treatment approaches used in the past, such as
vasodilatators or free radical scavengers were given under the assumption that tinnitus is
generated in the cochlea. Even among those drugs which are currently under development for
tinnitus (see next section and table 2), the cochlea is still the main target. This is even more
astonishing since the observed changes in neural function, such as increased firing rate or
increased synchrony should represent easier targets for pharmacological interventions than hair
cell damage in the cochlea. Why is this cochlear approach so persistently followed if it has not
been proven successful in the past, especially since there has been strong evidence for tinnitusrelated changes in the brain for more than a decade now (172;173)? One explanation may be
that some of the drugs under development mainly aim to prevent hearing loss or to treat it at
early stages. For this purpose the cochlea is probably the most promising target and successful
pharmacologic treatment of acute hearing loss has probably also beneficial effects on
accompanying tinnitus.
Langguth et al.
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Another explanation may be the fact that the most widely used animal model for tinnitus is
salicylate induced tinnitus. Since it has been assumed for years that salicylate produces tinnitus
by interfering with neural transmission in the cochlea (95;96), pharmacologic interventions in
animals were primarily targeting the cochlea. Only recently it has been shown, that salicylate,
in addition to its effects on the cochlea, increases the gain in central auditory pathways (174).
This finding may contribute to move the focus of attention for pharmacologic treatment of
tinnitus further to the central nervous system. Tinnitus related changes of central nervous
system activity are regulated by a variety of neurotransmitters such as GABA, glutamate or
serotonin, which can be modulated by pharmacologic treatment. Relatively strong, but only
transient effects on tinnitus have been reported after intraveneous lidocaine. Some
antidepressants and anticonvulsants seem to have moderate effects in subgroups of tinnitus
patients. So there are some hints indicating that activity-driven changes underlying tinnitus can
be pharmacologically targeted.
An important step towards designing a successful strategy in the search for tinnitus drugs
should include criteria to stratify or classify tinnitus patients included in trials. As previously
discussed, tinnitus often occurs as a result of insults to the ear, such as from noise exposure or
from administration of specific pharmacologic agents. It can also be caused by ear or head
injuries, some diseases of the ear and ear infections (19;175). In some cases the causative agent
remains unknown. The identification of the triggering cause may be of importance for selecting
the most adequate pharmacological approaches. Moreover, the manifestation of tinnitus can
vary, ranging from intermittent tinnitus perception with little impact on daily life to a
devastating roar that occurs 24 hours a day preventing sleep, the ability to do intellectual work,
leading to social isolation. Tinnitus is also often associated with other symptoms, such as
hyperacusis and distortion of sounds (175). Affective disorders, such as anxiety, phonophobia
and depression, often accompany severe tinnitus and that form of tinnitus can lead to suicide.
With such differences in etiology and symptoms, heterogeneity within tinnitus patients is
expected. Specific pathophysiological mechanisms have already been identified for specific
clinical factors such as the perceived localization (21;24), the duration (25;176) or the
frequency composition (177). Differential diagnosis of triggering events and temporal onset
should allow for a more rational and efficacious pharmacological approach. The fact that a
subgroup of patients who have intermittent tinnitus that sounds like a typewriter, pop corn or
ear clicking receive significant benefit from carbamazepine (82;83), indicates that subtyping
tinnitus is highly recommended. Efforts towards establishing subgroups of tinnitus are under
way (11;178;179), and will most likely aid the post-hoc identification of responders to specific
drugs and the selection of patients in future clinical trials.
Another strategy to address the lack of good fortune in drug discovery may be systematic
study of normal auditory physiology. Pharmacologic modulation of auditory signal processing
may yield useful clues as to the action of putative drugs for tinnitus treatment.
Advances in the understanding of tinnitus pathophysiology reveal a large number of similarities
with other disorders of the central nervous system, such as chronic pain, epilepsy, posttraumatic
stress disorder or affective disorders, suggesting that pharmacologic targets for the treatment
of these disorders may also represent promising candidates for treating tinnitus. Thus, for a
new compound, which is under development for any of these conditions, additional testing for
tinnitus may be warranted.
7. Competitive environment
There are only a small number of drugs in development for the treatment of tinnitus. However,
tinnitus can be found attached to long lists of indications in many more patents filed on
molecules aimed at a range of diverse therapeutic classes. A search carried out in the
Langguth et al.
Page 12
investigational drugs databases Pharmaprojects (www.pharmaprojects.com), AdisInsight

(www.adisinsight.com), Prous DDR (www.prous.com) and IDdb3
(http://science.thomsonreuters.com), shows that only a small number of compounds is
currently developed for tinnitus (Table 2). Neramexane acts as a non-competitive, voltagedependent NMDA antagonist and also blocks 910 nicotinic cholinergic receptors which are
expressed on hair cells in the inner ear (180182). After obtaining positive results from a Phase
II trial (http://clinicaltrials.gov/ct2/show/NCT00405886), Merz Pharmaceuticals is currently
conducting Phase III multi-center clinical trials to determine the efficacy, safety and tolerability
of Neramexane for treating tinnitus (http://clinicaltrials.gov/ct2/show/NCT00739635,
http://clinicaltrials.gov/ct2/show/NCT00772980,
http://clinicaltrials.gov/ct2/show/NCT00827008).
LidoPAIN TV is a non-sterile patch delivering lidocaine, which is applied to the periauricular
skin region. According to the companys web page, it demonstrated efficacy in a clinical proofof-concept study and has been in phase II trials for tinnitus.
The orally active drug SPI-1005 contains ebselen which acts as an antioxidant by stimulating
glutathione peroxidase. It has completed a phase I trial and phase II trials are planned for the
treatment of noise-induced hearing loss and tinnitus.
AM 101 is an NMDA antagonist, which is applied topically to the cochlea by round window
injection for the treatment of acute tinnitus. In a randomized, double-blind placebo-controlled
German Phase I/II trial in 24 patients with acute tinnitus following noise trauma or sudden
deafness, single-dose AM-101 intratympanic injection was well tolerated. It also had a positive
effect on tinnitus loudness and showed a trend in the tinnitus handicap as measured with the
TBF-12 questionnaire. Currently a double-blind, randomized, placebo-controlled Phase II trial
with cochlear application of AM-101 is being carried out. The study involves patients with
acute (<3 months) noise-induced tinnitus that have not responded to glucocorticoid treatment
(http://clinicaltrials.gov/ct2/show/NCT00860808). The same company has also a second
compound under development (AM-102). This compound is of unidentified pharmacologic
activity and is also delivered by intratympanic application. It is currently in preclinical tests.
Vestipitant is a novel antagonist of the neurokinin-1 (NK-1) receptor which binds substance
P. Neurokinin receptors are present in the inner ear and therefore represent a potential
therapeutic target for tinnitus (183). Vestipitant and the combination of vestipitant and
paroxetine are currently undergoing a phase II clinical trial for the treatment of tinnitus
(http://clinicaltrials.gov/ct2/show/NCT00394056).
EGb-761 is a concentrated extract of Ginkgo biloba, enriched in flavonoids and terpenes, which
has a broad spectrum of pharmacologic actions, including a free-radical scavenger effect and
which has shown efficacy for tinnitus in a phase I trial.
8. Potential development issues

Why is the number of companies with tinnitus compounds in their pipelines so limited in spite
of the existence of such a huge market for a clinically unmet need? One reason is probably that
the lack of serendipitous discoveries of effective treatments has severely limited insight into
tinnitus pathology. An additional challenge in the design of drugs for the treatment of tinnitus
derives from the fact that the neural substrates underlying tinnitus are far from being fully
understood. Increase in spontaneous firing rates or neuronal synchrony in different parts of the
auditory pathway as well as changes in cortical tonotopy have been proposed as potentials
correlates of tinnitus (19;35). Modern drug discovery is mainly focusing on the identification
of new chemical entities that interact with discrete molecular targets. This reductionist
approach requires the knowledge of defined sites of drug action with known clinical relevance.
Langguth et al.
Page 13

Thus, it is the absence of a fully-determined neuronal correlate/s for tinnitus that makes research
into this area potentially very high-risk. However even if a well-defined neuronal target would
ease the path towards drug discovery, the empirical approach that has been used for most central
nervous system disorders should not be precluded in the case of tinnitus. Most innovative
central nervous system acting drugs were discovered serendipitously (184). Before a compound
is judged suitable for testing in humans, it must first demonstrate safety and efficacy in animal
models. A drawback in the development of a tinnitus drug is the lack of in vitro bioassays or
validated animal models in which to test or screen for compounds. The basic dilemma faced
by the animal researcher who wants to study tinnitus is whether or not the animals have tinnitus
(87;97). An additional challenge is imposed by the fact that, in humans, tinnitus is accompanied
by the activation of a distress network that involves the limbic system (25;185), which is
probably not recapitulated in the animal models. Different animal models have been developed
and validated for acute tinnitus perception (97;164;171;186;187). However, it is questionable
to which extent results from the currently available animal models can predict effectiveness of
a drug on severity of chronic tinnitus in humans. Thus, there is a clear need for developing
animal models of chronic tinnitus which also include detection of the extent of tinnitus-evoked
emotional or cognitive changes. On the other hand, even in diseases where there is a greater
mechanistic understanding, there are still significant disparities between the animal models
used in discovery validation and the human diseases being targeted for treatment (188). Also,
if we look at animal models that have been developed for even more complex central nervous
diseases such as depression or schizophrenia, they have proven useful, even if they can serve
only as models of disease mechanisms but not of the disease itself. Thus, the search for drugs
to treat tinnitus should not wait for a complete understanding of the neural correlates of tinnitus
nor the refinement of the animal models. Finally, because the first tinnitus drugs are yet to be
approved, regulatory agencies such as the Food and Drug Administration (FDA) or the
European Medicines Agency (EMEA), lack standardized protocols for their approval process.
Therefore, the first pharmaceutical industry to develop a tinnitus drug will have to pave the
way. This will be most successful as a collaborative effort with tinnitus researchers providing
informed direction to drug companies and developing better lines of communication.
In addition, tinnitus being a subjective phenomenon, assessment of outcome is probably the

single most important factor in conducting a clinical trial. Thus, definition of outcome
measurements is not trivial, but probably critical for the design of clinical trial. A
comprehensive evaluation includes the assessment of (1) tinnitus loudness, either by visual
analogue scales or by psychoacoustic measurements and (2) of tinnitus severity, which is
usually assessed by validated questionnaires. However since psychoacoustic measures of
tinnitus loudness have shown only limited test- retest reliability (12) and only a low correlation
with perceived tinnitus severity or annoyance (189;190) there is increasing consensus among
clinical researchers, that psychoacoustic tests are only of limited value for outcome
measurement (11). On the other hand it has been argued, that treatment interventions that aim
to reduce tinnitus loudness, should not only be assessed by questionnaires of tinnitus annoyance
but also by loudness measurements (179). Furthermore, it has to be considered that
questionnaires for assessment of tinnitus severity have not been designed and validated for
evaluating treatment induced changes. Thus, it is not clear to which extent these questionnaires
are sensitive to treatment induced changes, especially since answer options in different
questionnaires vary between 3-point ordinal scales (191;192) and 0100 interval scales (193).
Moreover most of the questionnaires have been validated by using the Beck Depression
Inventory (BDI) and therefore their scores correlate highly with the BDI scores (29). Hence,
in a sample of tinnitus patients with comorbid depression, a drug that has an antidepressant
effect, but no effect on tinnitus would probably result in reduced tinnitus scores, just by
reducing depressive symptoms.
Langguth et al.
Page 14
9. Expert opinion
Currently no drug is available that has demonstrated replicable, long-term reduction of tinnitus
impact in excess of placebo effects. However, there is an urgent need for efficacious compounds
and there is no reason to believe, that tinnitus cannot be effectively treated by pharmacotherapy.
The development of behavioral measures of tinnitus in animals, together with molecular,
biochemical, physiological, and imaging techniques are offering increasing insights into the
underlying causes of tinnitus and to identify new potential targets for treatment. Moreover,
animal models will provide a way to screen for new compounds that can suppress tinnitus.
Imaging in combination with detailed standardized assessment will help to identify specific
tinnitus subtypes that respond to specific treatments. Also efforts have been made to find
consensus about patient assessment and outcome measures (11). These important advances in
tinnitus research during the last years clearly indicate that those difficulties which currently
hamper the search for effective pharmacologic treatment are solvable in the near future. The
market for a tinnitus drug is already huge, untapped and likely to grow. Thus, looking towards
a promising future, patients and clinicians may finally receive encouraging news if more and
more compounds will be tested for tinnitus and if any of the compounds under development
will reach the market. The availablility of an approved drug will enlarge therapeutical
possibilities. It is also possible that the therapeutic value of certain drugs may be enhanced if
used in combination with masker/sound therapy together with cognitive behavioural therapy.
A major turning point or water shed event in the treatment of tinnitus, likely to occur in the
next few years, is the FDA or EMEA approval of a drug to treat tinnitus and its debilitating
side effects.
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Langguth et al.
Page 24
Table 1
Number of prescriptions prescribed in 2001 in primary care for the diagnosis of tinnitus in Western Europe *.

Substance
Number of prescriptions in 2001 (in Thousands)
ginkgo biloba
782
trimetazidine
650
betahistine
314
pentoxifylline
312
piracetam
197
naftidrofuryl
184
buflomedil
144
cinnarizine
141
clonazepam
137
nicergoline
119
dihydroergocristine
91
flunarizine
73
nimodipine
56
Acetylsalicylic acid
53
hetastarch
50
ajmalicine
42
moxaverine
32
piribedil
31
almitrine
21
prednisolone
21
amitriptyline
21
dihydroergocryptine
18
cinnarizine
18
caffeine
16
mesoglicane
14
Vitamin E
14
dihydroergotixine
14
retinol
13
cyclandelate
12
gold
10
Viscum album
10
Hypericum perforatum
10
Number of prescriptions prescribed in 2001 in primary care for diagnosis of tinnitus in Western Europe (UK, France, Germany, Spain, Italy,
Netherlands, Belgium, Denmark, Finland, Austria, Greece, Portugal, Republic of Ireland and Switzerland) (only substances with at least 10000
prescriptions are included)

Auris Medical
Auris Medical
Glaxo-Smith-Kline
Ipsen
AM-101
AM-102
Vestipitant + paroxetine
EGb-761
Epicept
LidoPAIN TV
Sound pharmaceuticals
Merz
Neramexane
SPI-1005 / ebselen
Company
Compund
Cognitive disorder, Alzheimers disease, vertigo,

tinnitus
Depression, anxiety, tinnitus
Prevention and treatment of tinnitus
Tinnitus and hearing loss
Prevention and treatment of noise induced hearing loss

and tinnitus
Tinnitus, vertigo
Tinnitus, Alzheimers disease, nystagmus, pain
Indication
Phase I
Phase II
preclinical
Phase II
PhaseII
Phase II
Phase III
Stage of development
Drugs under development for tinnitus
Free radical scavanger
neurokinin-1 (N K-1) receptor antagonist + serotonine reuptake

inhibitor
Unidentified pharmacological activity
NMDA antagonist
antioxidant
Local anesthetic of periauricular nerve endings
NMDA receptor antagonist, blocker of alpha9 and alpha10

nicotinic cholinergic receptors
Mechanism of action
Table 2
Langguth et al.
Page 25

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